Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission

Al-Mubarak, Bashayer; Omar, Aisha; Baz, Batoul; AlAbdulaziz, Basma S.; Magrashi, Amna; Alyemni, Eman A.; Jabaan, Amjad; Monies, Dorota; Abouelhoda, Mohamed; Abebe, Dejene; Ghaziuddin, Mohammad; Tassan, Nada Al

doi:10.1038/s41431-020-0619-7

Cited by 22 publications

(15 citation statements)

References 49 publications

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“…We detected 9 Hi-C coupled gene-neuron associations in male suicidality GEWIS ( Table S18 ). Two of these have been previously associated with psychopathology: UBE2E3 -neuron ( z a = 4.25, p a = 1.07 × 10 −5 , z int = 4.42, p int = 4.89 × 10 −6 ) previously associated with bipolar disorder, smoking behavior, and hurt ( McCarthy et al, 2014 ) feelings; MORC3 -neuron ( z a = 4.16, p a = 1.58 × 10 −5 , z int = 4.42, p int = 4.99 × 10 −6 ) previously associated with frequency of tiredness and depressive symptoms; and DOP1B -neuron ( z a = 4.16, p a = 1.58 × 10 −5 , z int = 4.42, p int = 4.99 × 10 −6 ) previously implicated in neurological disorders and dystonias ( Al-Mubarak et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality

Wendt

Pathak

Levey

et al. 2021

Neurobiology of Stress

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Epidemiologic studies recognize that trauma and posttraumatic stress are associated with heightened suicidal behavior severity, yet examination of these associations from a genetic perspective is limited. We performed a multivariate gene-by-environment genome-wide interaction study (GEWIS) of suicidality in 123,633 individuals using a covariance matrix based on 26 environments related to traumatic experiences, posttraumatic stress, social support, and socioeconomic status. We discovered five suicidality risk loci, including the male-associated rs2367967 ( CWC22 ), which replicated in an independent cohort. All GEWIS-significant loci exhibited interaction effects where at least 5% of the sample had environmental profiles conferring opposite SNP effects from the majority. We identified PTSD as a primary driving environment for GxE at suicidality risk loci. The male suicidality GEWIS was enriched for three middle-temporal-gyrus inhibitory neuron transcriptomic profiles: SCUBE - and PVALB -expressing cells ( β = 0.028, p = 3.74 × 10 −4 ), OPRM1 -expressing cells ( β = 0.030, p = 0.001), and SPAG17 -expressing cells ( β = 0.029, p = 9.80 × 10 −4 ). Combined with gene-based analyses ( CNTN5 p association = 2.38 × 10 −9 , p interaction = 1.51 × 10 −3 ; PSMD14 p association = 2.04 × 10 −7 , p interaction = 7.76 × 10 −6 ; HEPACAM p association = 2.43 × 10 −6 , p interaction = 3.82 × 10 −7 ) including information about brain chromatin interaction profiles ( UBE2E3 in male neuron p = 1.07 × 10 −5 ), our GEWIS points to extracellular matrix biology and synaptic plasticity as biological interactors with the effects of potentially modifiable lifetime traumatic experiences on genetic risk for suicidality. Characterization of molecular basis for the effects of traumatic experience and posttraumatic stress on risk of suicidal behaviors may help to identify novel targets for which more effective treatments can be developed for use in high-risk populations.

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Section: Resultsmentioning

confidence: 99%

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality

Wendt

Pathak

Levey

et al. 2021

Neurobiology of Stress

View full text Add to dashboard Cite

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“…On the other hand, the significant genetic correlations between ADHD and certain somatic traits or diseases (such as weight and weight-related traits, smoking-related cancer, and reproductive traits) reveal a great degree of overlap between the genetic risk factors (Demontis et al, 2019). At this point, it is important to mention that current results support that non-coding variants, such as intronic indels, have been shown to play an important role (Liu et al, 2021) not only in identifying ADHD risk genes (Al-Mubarak et al, 2020), but also for medical diseases (Tan, 2020), as the non-coding elements can regulate the transcription and translation of protein-coding genes. Consistently, recent recommendations for complex, neurodevelopmental disorders increasingly raise the usefulness of whole genome analysis, since the identification of the underlying genetic etiology between neurodevelopmental and somatic conditions can provide a more precise clinical management impacting patient care.…”

Section: Therapeutic Aspectsmentioning

confidence: 66%

Genetics in the ADHD Clinic: How Can Genetic Testing Support the Current Clinical Practice?

2022

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Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a childhood prevalence of 5%. In about two-thirds of the cases, ADHD symptoms persist into adulthood and often cause significant functional impairment. Based on the results of family and twin studies, the estimated heritability of ADHD approximates 80%, suggests a significant genetic component in the etiological background of the disorder; however, the potential genetic effects on disease risk, symptom severity, and persistence are unclear. This article provides a brief review of the genome-wide and candidate gene association studies with a focus on the clinical aspects, summarizing findings of ADHD disease risk, ADHD core symptoms as dimensional traits, and other traits frequently associated with ADHD, which may contribute to the susceptibility to other comorbid psychiatric disorders. Furthermore, neuropsychological impairment and measures from neuroimaging and electrophysiological paradigms, emerging as potential biomarkers, also provide a prominent target for molecular genetic studies, since they lie in the pathway from genes to behavior; therefore, they can contribute to the understanding of the underlying neurobiological mechanisms and the interindividual heterogeneity of clinical symptoms. Beyond the aforementioned aspects, throughout the review, we also give a brief summary of the genetic results, including polygenic risk scores that can potentially predict individual response to different treatment options and may offer a possibility for personalized treatment for the therapy of ADHD in the future.

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“…For example, Farrer et al identified three independent loci on chromosomes 9, 10, and 12 determining Alzheimer's disease in an Israeli–Arab community with a high consanguinity rate and a familial structure resembling the one found in Sudanese families ( 26 ). Moreover, Al-Mubarak et al found at least two likely pathogenic variants in the majority of probands with attention deficit hyperactivity disorder (ADHD) in Saudi Arabia, leading to the conclusion that ADHD should be considered as a complex disorder ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Involvement of ADGRV1 Gene in Familial Forms of Genetic Generalized Epilepsy

et al. 2021

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Background: Genetic generalized epilepsies (GGE) including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures alone (GGE-TCS), are common types of epilepsy mostly determined by a polygenic mode of inheritance. Recent studies showed that susceptibility genes for GGE are numerous, and their variants rare, challenging their identification. In this study, we aimed to assess GGE genetic etiology in a Sudanese population.Methods: We performed whole-exome sequencing (WES) on DNA of 40 patients from 20 Sudanese families with GGE searching for candidate susceptibility variants, which were prioritized by CADD software and functional features of the corresponding gene. We assessed their segregation in 138 individuals and performed genotype–phenotype correlations.Results: In a family including three sibs with GGE-TCS, we identified a rare missense variant in ADGRV1 encoding an adhesion G protein-coupled receptor V1, which was already involved in the autosomal recessive Usher type C syndrome. In addition, five other ADGRV1 rare missense variants were identified in four additional families and absent from 119 Sudanese controls. In one of these families, an ADGRV1 variant was found at a homozygous state, in a female more severely affected than her heterozygous brother, suggesting a gene dosage effect. In the five families, GGE phenotype was statistically associated with ADGRV1 variants (0R = 0.9 103).Conclusion: This study highly supports, for the first time, the involvement of ADGRV1 missense variants in familial GGE and that ADGRV1 is a susceptibility gene for CAE/JAE and GGE-TCS phenotypes.

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Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission

Cited by 22 publications

References 49 publications

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality

Genetics in the ADHD Clinic: How Can Genetic Testing Support the Current Clinical Practice?

Involvement of ADGRV1 Gene in Familial Forms of Genetic Generalized Epilepsy

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